Project Summary/Abstract: Breast cancer remains a considerable health concern. With the recent increase in affordible multi-gene germ line testing, an estimated 0.5-1 million women, many very young, will be in need of intense breast cancer screening and prevention options. Options to prevent breast cancer in women with high risk currently include bilateral mastectomies, or anti-estrogen therapy and premature menopause. For most women, these are grim choices. Localized delivery of an anti-estrogen to breast tissue may be an attractive alternative for cancer prevention and may further provide an alternative to systemic therapy for ductal carinoma in situ (DCIS) and early stage breast cancer with minimal risk for metastasis. We, therefore, propose the use of a silastic-silicone device placed under breast tissue as a local delivery strategy for anti-estrogen therapy. The slow release of an anti-estrogen from silastic-silicone directly into the breast parenchyma with preferential breast tissue uptake will achieve a high local concentration while minimizing systemic exposure. In preliminary in vitro and in vivo data, we show that approved anti-estrogens can be delivered through an implantable silastic-silicone device that provide sustained high levels of drug that inhibit estrogen receptor (ER) signaling and breast cancer cell proliferation. Silastic-silicone delivers fulvestrant selectively to mouse mammary tissue for more than 1 year with anti-tumor effects similar to those acheived with systemic fulvestrant exposure. In this application, we propose to test and refine this localized drug delivery strategy in an inducible prevention model and large animal model. In three specific aims, we will (Aim 1) determine the efficacy of silastic-silicone released fulvestrant to prevent tumor formation in an inducible rat breast cancer model and establish estradiol-PET imaging as a co-diagnosic for tumor ER modulation, and (Aims 2 and 3) optimize the design of the device, characterize drug diffusion and penetration properties in tissue utilizing a large animal goat model. These experiments will lay the ground work for rapid clinical translation to initial safety and efficacy studies in a breast cancer DCIS setting with a companion imaging biomarker. The greater awareness and genetic identification of individuals at risk for breast cancer comes with an increased need for new approaches to breast cancer prevention. The development of a silastic-silicone based device for sustained local drug delivery with an approved and effective anti-estrogen should allow rapid transition into clinical testing. This strategy will provide an alternative option to delay or forgo mastectomies to the rapidly increasing number of young women identified to have a more than 40% lifetime chance of developing breast cancer. If successful this therapeutic approach should be transferable to other tumors and a broader range of anti-cancer agents.